Production/Formulation, Design, Process Development and Pilot-Scale Testings

1
Production/Formulation, Design, Process
Development and Pilot-Scale Testings A.
Preformulation 1. Background Information
2. Bulk Characterization 3. Solubility
Analysis 4. Stability and Compatibility B.
Formulation Studies 1. Formulation Design and
Trial Manufacturing 2. Package Development
and Comparative Stability 3. Process
Development, Proposed Product Pilot Testing,
Stability Studies, and Master Batch Documentation
Development
2
A. Preformulation ???? It can be defined as an
investigation of physical and chemical properties
of drug substancesalone and combined with
excipients. Collecting information For
developing stable and bioavailable dosage forms
Beginning in the early development of a new
drug substances (biological screening stage,
?????) For selecting an suitable candidate
(new compound) for further development.
3
1. Background Information Chemical
structure, Different salts Therapeutic
class and anticipated dose Supply situation
and development schedule Stability-indicatin
g assay Nature information Organoleptic
properties, Purity Essential Information a.
Compound identity b. Structure
c. Formula and MW d.
Therapeutic indication Probable human dose,
Desired dosage forms, Bioavailability models,
Competitive products
4
e. Potential hazards f.
Initial bulk lots g. Analytical Methods
GC-MS, HPLC-tandem MS, HPLC, TLC, UV/VIS
spectroscopy, Synthetic route, Probable decay
products h. Key dates Bulk scale-up,
Toxicology start date, Clinical supply
preparation, IND filing, Phase I testing
i. Critical development issues
5
Salts used in Pharmaceutical Products in the USA
(through 1974) Anion
Anion Anion
Acetate 1.26
Benzenesulfonate 0.25 Benzoate
0.51 Bicarbonate 0.13
Bitartrate 0.63 Bromide
4.68 Calcium edetate
0.25 Camsylate 0.25
Carbonate 0.38 Chloride
4.17 Citrate
3.03 Dihydrochloride
0.51 Edeate 0.25
Edisylate 0.38 Estolate
0.13 Fumarate
0.25 Gluceptate 0.18
Gluconate 0.51 Glutamate
0.25 Glycollylarsanilate
0.13 Hexylresocinate
0.13 Hydrobamine 0.25
Hydrobromide 1.90 Hydrochloride
42.98 Hydroxynaphthoate 0.25
Iodide 2.02 Isethionate
0.88 Lactate
0.76 Lactobionate 0.13
Malate 0.13 Maleate
3.03 Mandelate
0.38 Mesylate
2.02 Methylbromide 0.76
Methylnitrate 0.38 Methylsulfate
0.88 Mucate
0.13 Napsylate 0.25
Nitrate 0.64

6
Salts used in Pharmaceutical Products in the USA
(through 1974) Anion
Anion Anion
Pamoate (Embonate) 1.01 Pantothenate
0.25 Phosphate/diphosphate
3.16 Polyglacturonate 0.13
Salicylate 0.88 Stearate
0.25 Subacetate
0.38 Succinate 0.38
Sulfate
7.46 Tannate 0.88
Tartrate 3.54 Teoclate
0.13 Tiethiodide
0.13 Cation Cation
Cation
Organic Benathine 0.66
Chloroprocaine 0.33 Choline
0.33 Diethanolamine
0.98 Ethylenediamie 0.66
Meglumine 2.29 Procaine
0.66 Metallic Aluminum
0.66 Calcium 10.49
Lithium
1.64 Magnesium 1.31
Potassium 10.82 Sodium
61.97 Zinc
2.95
7
Organoleptic Properties of Pharmaceutical
Powders Color Odor
Taste Off white
Pungent Acidic Cream yellow
Sulfurous Bitter Tan
Fruity
Bland Shiny
Aromatic Intense
Odorless
Sweet
Tasteless
8
2. Bulk Characterization Crystallinity and
Polymorphism Hygroscopicity Fine
Particle Characterization Bulk Density
Powder Flow Properties Crystallinity and
Polymorphism ???? ? ???? Habit the outer
appearance of crystal Internal Structure
the molecular arrangement within solid
Characterization of a solid form a.
Verifying the solid b. Characterizing the
internal structure c. Describing the
habit of the crystal
9
Chemical Compound Habit
Internal
Structure
Crystalline
Amorphous Single entity
Molecular Adducts polymorphs

Nonstoichiometric
stoichiometric
Inclusion compounds solvates (hydrates)
Channel Layer
Cage (Clathrate)
Outline of differentiating habit and crystal
chemistry of a compound
10
Different habits
11
Analytical Methods for Characterization of Solid
Forms (Methods and material required) Microscopy
1 mg Using polarizing
filters, Isotropic single refractive

index anisotropic 2 refractive indices Fusion
Methods 1 mg With polarizing
filters for investigating

polymorphism, mp, transition temperature, rate

of transition Differential Scanning
Calorimetry 2-5 mg Impurity, heat of
fusion , transition of

polymorph Infrared Spectroscopy 2-20 mg
Scanning Electromicroscopy 2 mg SEM,
polymorphism, solvate Thermogravimetric Analysis
10 mg Measuring change in sample weight,

desolvation, decomposition Dissolut
ion Solubility Analysis mgg
12
(No Transcript)
13
(No Transcript)
14
Thermogravimetric (TGA) for an acetate salts of
an organic amine with two crystalline forms,
anhydrous and dihydrate.
15
Differential scanning calorimetric (DSC) for an
acetate salts of an organic amine with two
crystalline forms, anhydrous and dihydrate.
16
Amorphous epicillin anhydrous
Powder X-ray diffraction patterns
17
Polymorphism Enatiotropic One polymorph can
be reversibly changed into another by varying
temperature or pressure Polymorphic
transition Important in processing (drying)
suspension dosage forms, and solid dosage forms
Transition Temperature The temperature for
changing one polymorph to another.
For determining transition T is microscopic
observation of samples held at constant
temperatures. Solubility-temperature
diagrams.
18
(No Transcript)
19
Hygroscopicity (???) Deliquescent
(???)materials adsorbed sufficient water to
dissolve completely, such as sodium chloride,
lithium chloride. Lithium chloride
(dissolved and solid phase), 20 C, 15 RH
Determining Hygroscopicity Samples of bulk
drug placed in open containers with a thin powder
bed to assure maximum exposure. The samples are
then exposed to a range of controlled RH
environment prepared with saturated aqueous salt
solutions. Percentage-of-weight-gain data are
plotted against time. Fine Particle
Characterization Particle size, Shape,
and surface morphology
20
Microscope gt 3 microns, providing adequate
size and shape characterization. Coulter
Counter particles dispersed in isotonic saline
and determined from 0.4 to 800 microns.
Sedimentation Method Andreasen pipet or
particle analyzer. Determination of Surface
Area BET method (Brunaurer, Emmet and Teller
theory), a layer of nitrogen molecules in
adsorbed to the sample surface at 196 C, liquid
nitrogen boiling point (16 square Å/Nitrogen
molecule). Surface Morphology SEM
21
(No Transcript)
22
Solubility of hydrocortisone and hydrocortisone
21-heptanoate in propylene glycol-water mixture
23
Bulk Density Apparent bulk density determined
by pouring presieved (40-mesh) bulk drug into a
graduated cylinder via a large funnel and
measuring the volume and weight. Tapped
density determined by placing a graduated
cylinder containing a known mass of drug or
formulation on a mechanical tapper apparatus
which is operated for a fixed number of taps
(about 1000) until the powder bed volume has
reached a minimum. Bulk density is important
for the size of capsule product.
24
Powder Flow Properties Affecting Factors
particles size, density, shape, electrostatic
charge and adsorbed moisture. Static Angle of
Repose 25-45, lower value indicating better flow
characteristics.
The apparatus for measuring angle of repose.
25
Flow rate apparatus A grounded metal tube,
drug flows through an orifice onto an electronic
balance which connected to a strip chart
recorder. Flow rate (g/sec) is determined at
each of a variety of orifice sizes (1/8 to ½
inch). Compressibility The ability of powder
to form a compact under pressure.
compressiblity 100 (Dt - Di) /Dt Dt
tapped bulk density Di initial bulk
density
26
Compressibility and Flowability of
Pharmaceutical Excipients Compressibility
Flowability Compressibility
Flowability 5-15
Excellent 12-16
Good 18-21
Fair-Passable 23-35
Poor 33-38 Very
poor lt40
Very, very poor Material
Flowability Material
Flowability Celutab 11
Excellent Emcompress 15
Excellent Star X-1500 19
Fair-passable Lactose H2O 19
Fair-passable Maize Starch 26-27 Poor
Dicalcium phosphate 2 H2O
(coarse)

27 Poor Magnesium stearate 31
Poor Titanium dioxide 34
Very poor Dicalcium Phosphate, 2 H2O (fine)
41 Very,
very poor Talc 49
Very, very poor
27
3. Solubility Analysis Solid drugs
administrated orally for systemic activity must
dissolve in the GI fluids prior to absorption.
Compounds with an aqueous solubility of
greater than 1 w/v are not expected to present
dissolution-related absorption problem.
Media isotonic chloride and acidic pH
0.9 NaCl 0.01 N HCl
0.1 N HCl 0.1 M NaOH,
pH 7.4 buffer at 37
C Solubility Studies pKa, temperature
effect, pH solubility profile, solubility
products, solubilization mechanisms and rate of
dissolution.
28
Solubility Measurements HPLC,
UV spectroscopy, Fluorescent spectroscopy and
Gas chromatography pKa determinations
For acidic compounds pH
pKa log (ionized drug)/(un-ionzed drug)
For basic compounds
pH pKa log (un-ionzed drug)/(ionized
drug) Methods determining the
spectral shifts by UV or visible
spectroscopy, Potentiometric
titration
COOH
29
Effect of Temperature Endothermic
increasing temperature, increasing solubility
Exothermic increasing temperature,
decreasing solubility ln S
-? Hs / RT C S
molar solubility at temperature T
R Gas constant ?Hs Heat of
solution
30
Plot of hydrochloride and free base solubilites
for etoxadrol, an organic amine
Etoxadrol Anesthetic
C6H5
O
C2H5
H N
31
Salt Solubility Different salts with
different characteristic equilibrium
solubilites. Apparent solubilities in water
at 25 C of salt form of ?-(2-piperidyl)-3,6-bis(tr
ifluoromethyl)-9-phenanthrene methanol
antimalarial agent Salt form
Apparent solubility (g/L)
Free base
0.0070.008 Hydrochloride
0.012-0.015 D,L-lactate
1.81.9
2-Hydroxyethane-1-sulfonate 0.62
Methanesulfonate 0.3
Sulfate
0.020
32
Solubilization Drug with poor water
solubility or insufficient solubility for
projects solution dosage forms, preformulation
studies need identify possible mechanism for
solubilization. Cosolvents, such as ethanol,
propylene glycol and glycerin may be used.
Partition Coefficient The gastrointestinal
membranes are largely lipoidal in character, the
lipid solubility of a drug is an important factor
in the assessment of its absorption potential.
The partition coefficient is defined as the
ratio of un-ionized drug distributed between the
organic and aqueous phases at equilibrium
Po/w Coil /Cwater Organic solvent
chloroform, ether, amyl acetate, n-octanol
33
Comparison between colonic absorption and
Lipid/water partition of the un-ionized forms of
barbiturates Barbiturates
Absorbed Chloroform/water Barbital
12
0.7 Aprobarbital
17 4.0 Phenobarbital
20
4.8 Allylbarbituric acid 23
10.5 Butethal
24
11.7 Cyclobarbital 24
18.0 Pentobarbital
30
23 Secobarbital R1allyl 40
50.7 Hexethal
44 gt100.0
H
N
O
O
R1
N
R2
O
R1 -C2H5 -allyl
34
Dissolution Factors for affecting
dissolution of drug particles
Chemical form Crystal habit
Particle size Solubility
Surface area Wetting properties
Noyes-Whitney equation dC/dt
DA/hV (Cs C) D diffusion
coefficient h thickness of the
diffusion layer A Surface area
of drug Cs Saturated
concentration Intrinsic dissolution rate
constant can be determined using a constant
surface area dissolution apparatus. K D/h
Cs
35
Constant-surface assembly for the determination
of intrinsic dissolution rates
36
(No Transcript)
37
4. Stability Analysis Stability studies
include both solution and solid state experiments
under condition typical for the handling,
formulation, storage, and administration of a
drug. A meaningful chemical stability study
need a specific assay. Stability in
toxicology formulation Solution stability
The effects of pH, ionic strength, cosolvent,
light, temperature and oxygen The
extremes pH and temperature (0.1 N HCl, water and
0.1 N NaOH all at 90 C) for confirming decay.
Assay specificity and for estimating maximum
rates of degradation.
38
The ionic strength of an isotonic 0.9 sodium
chloride solution is 0.15. Cosolvent selected
from the alcohol family. Solution is studied
in flame-sealed ampoules and stored in variety of
temperatures. In light stability test, solution
is packaged in amber and yellow-green glass
containers. For oxidation, samples are tested
as following a. With excessive headspaces
of oxygen b. With a headspace of and inert
gas such as helium or nitrogen c. With an
inorganic antioxidant, such as sodium
metabisulfite d. With organic antioxidant,
such as BHT (butylated hydroxytoluene)
39
Sample scheme for determining the bulk stability
profile Storage Condition 4
8 12 weeks 5 C
Refrigerator 22 CRoom temperature 37 CAmbient
Humidity 37 C/ 75 RH Light Box Control, Clear
Glass, Amber Glass, Yellow-green Glass 50
CAmbient Humidity, O2 Head Space, N2 Head
Space 70 CAmbient Humidity 90 CAmbient Humidity
40
An Arrhenius plot is constructed by plotting the
logarithm of the apparent decay rate constant
versus the reciprocal of the absolute
temperature. ln K - Ea/RT C
Ln K
Slope -Ea/R
Shelf-life (t10 ) is calculated from the
following equation t10 - ln 0.90/K 0.105
/K
1/T ( oK)
41
Solid State Stability The objectives are used
to identify stable storage condition for drug in
the solid state and identify compatible
excipients for a formulation. Assay for
solid state reaction IR, DSC HPLC The
decay process may be analyzed by either
zero-order or first-order for less than 15-20
decay. Humidity affecting drug stability
KH gp1 Ko KH apparent
decay rate constant gp1 grams of water
per liter of dry air Ko decay rate
constant at zero RH
42
Compatibility Studies Tablet contains
binders, disintegrant, lubricants, and
fillers. Compatibility screening for a new
drug must consider two or more excipients from
each class. Thermal analysis (DSC, DTA)
is useful in the investigation of solid-state
interactions. Diffuse Reflectance
Spectroscopy
43
B. Formulation Studies 1. Formulation Design
and Trial Manufacturing 2. Package
Development and Comparative Stability 3.
Process Development, Proposed Product Pilot
Testing, Stability Studies, and Master Batch
Documentation Development
44
High-performance double rotary tablet
pressKorsch PharmapressR 1 million tablets/hr
(regularly 600,000800,000/hr)
45
(1). Formulation Design Trial Manufacturing
Example Tablets Tablet
Resistance to mechanical abrasion or friability,
rapid disintegration and dissolution.
Producing a safe, effective and highly reliable
products Tablet formulation and design
The process whereby the formulator insures
that correct amount of drug in the right form is
delivered at over the proper time at the proper
rate and in the desired location, while having
its chemical integrity protected to that point.

46
(I). Preformulation Studies 1. Stability
(solid state) light, temperature, humidity
2. Stability (solution) excipient-drug
stability 3. Physicomechanical properties
particle size, bulk and tap density, crystalline
form, compressibility, photomicrographs, melting
point, taste, color, appearance, odor. 4.
Physicochemical properties solubility and pH
profile of solution/dispersion 5. In vitro
dissolution pure drug, pure drug pellet,
dialysis of pure drug, absorability, effect of
excipients and surfactants.
47
(II). A Systemical Approach to Tablet Product
Design 1. Identification of the optimum site
for drug release along the gastrointestinal tract
for the particular drug 2. Identification of
the method of manufacture 3. Selection of
compatible formula candidate ingredients 4.
Preparation of trial formulations for in vitro
and in vivo evaluation
5. In vitro testing 6. In vivo testing in
animals and man, or man directly 7. Development
of stability, bioavailability, validation, and
other data as a required for new drug under an
NDA
48
(III). Tablet Compositions and Additives
Active Ingredients 1. General
considerations 2. Bioavailability
considerations Nonactive Ingredients
Diluents lactose USP lactose USP, anhydrous
lactose USP, spray-dried starch USP directly
compressible starch mannitol USP sorbitol
microcrystalline cellulose dibasic calcium
phosphate dihydrate sucrose-based diluent
sucrose USP powder calcium sulfate dihydrate
calcium lactate trihydrate granular
RC N
H
RCHO
H2N
COOC2H5
COOC2H5
49
Binders and Adhesives Disintegrants
Lubricants Water-insoluble Water soluble
Antiadherents Glidants
Colorants Flavors and Sweeteners
50
(IV). Methods of Manufacture Compressed
tablets Sublingual tablets, chewable
tablets, effervescent tablets, layer tables,
sustained-release products, sugar coated tablets,
film coating tablets, enteric-coated tablets.
Methods Wet granulation, dry granulation
and direct compression Wet granulation
Advantages 1. Improving the
cohesiveness and compressibility of powders
2. Suitable for high-dosage drugs having poor
flow or compressibility properties

51
3. Good distribution and uniform content
for soluble low dosage drugs and color additives
4. Preventing segregation of components of
a homogenous powder during processing,
transferring and handling 5. Possible
improving the dissolution rate of a hydrophobic
drug Limitation An expensive
process for labor, time, equipment, energy and
space requirements
52
Drug
Direct compression Tableting Advantages
1. Economy 2. Elimination of heat and
moisture 3. Prime particle dissociation
4. Stability 5. Particle size
uniformity Limitations Flow, bonding
of particles, coloring tablets
Grind
Blend
Compress
Tablet
Direct Compression
53
Dry Granulation Advantages 1. For
mositure-sensitive materials 2. For
heat-sensitive materials 3. For improving
disintegration since powder particles are not
bonded together by a binder 4. For
improving solubility, as with anhydrous soluble
materials that tend to set when wet 5. For
improving blending, since there is no migration
of ingredients might occur during the drying of
wet granulation
54
Disadvantages 1. It requires a
specialized heavy-duty tablet press to form the
slug 2. It does not permit uniform color
distribution as can be achieved with wet
granulation 3. A pressure roll press such
as the Chilsonator cannot be used with insoluble
drugs 4. The process tends to create more
dust than wet granulation
55
(VI). Problems in Tablet Manufacture 1. Binding
(binding in the die) Increase lubrication
Use more efficient lubrication Improve method
of addition of lubricant Increase moisture or
regranulate Modify granulation reduce granule
size Increase punch-die clearance Taper
dies Compress at lower temperature and.or
humidity
56
2. Sticking ( filming or picking, some granules
sticking to punch faces) Decreasing
moisture content of the granulation Change
or decrease the lubricant Increase the
proportion of binder in the granulation
Add an adsorbentmicrocrystalline cellulose,
silica gel, et al Clean punch faces with
5 light mineral oil in isopropanol
Polish punch faces on lathe with jewelers rouge
(?????)or fine emery cloth (?????) or chromium
plate punches
57
3. Capping and Lamination Remove some
or all of the fines through a 100 to 200 mesh
screen Increase or change lubricant
Reduce or change lubricant Dry or moisten
granulation, using moisture analysis to determine
limits Improve granulating procedure
Increase binder or wetting of the granulation
Taper dies 0.0005 to 0.002 inch, depending
on diameter Add dry binder Reduce
upper punch by 0.0005 to 0.001 inch
58
4. Chipping and cracking Replace or reface
nicked or chipped punches Reset table press
take-off Improve granulation by increasing
binder and/or by wetting of the granulation
Add dry binder or plasticizer such as PVP,
pregelatinized starch, powdered acacia, and
microcrystalline cellulose Polish punch
tips Remove some or all fines Reduce
granule size Reformulate to attempt to
eliminate expansion of table 5. Tablet Expansion
59
(2) Package Development Comparative
Stability The functions of a drug package
Containment Protection
Other Essential Functions
60
The package must provide some way to dispense the
contents, either into another container or
directly onto the hand or into the body. Some
provision must be made for reclosure of the
package so the unused contents will not lose
their potency or efficacy, become contaminated or
represent a hazard to small children. When the
package contents are sterile, this sterility must
be maintained, including the sterility of the
unused remainder. The package must present all
the information about the drug that is required
by law and good therapeutic practice.
61
The package should help sell over-the-counter
(OTC) products without the need for intervention
by a pharmacist. Although most packages do not
perform this function, packages which aid in
compliance pay large dividends in reduced
healthcare costs. The package design must
provide evidence of tampering for those products
which are so regulated by the FDA. Generally,
all OTC drugs fall into this category. Packages
for prescription drugs and certain OTC products
must thwart access by young children.
62
Frequency of use of various containers container
of total 1991
(Dollar Sales) Plastic
containers 24.7 Paperboard
containers 21.3 Blister packages
11.9 Labels and package
inserts 11.1 Plastic closures
10.8 Glass containers
7.1 Metal containers
4.0 Nonplastic closures
3.4 Miscellaneous
5.7
63
Packaging Needs Stability moisture,
oxygen, light Purity and Sterility
Packaging material not be a source of
contamination. Packaging material must
withstand the sterilization of manufacturing
process Drug Physiology A critical
packaging need for certain route Solid
Dosage Forms Preventing moisture or oxygen
pickup Liquids No leakage No
contamination Retention of sterility,
transparency. Ointment Means of convenient
and sanitary Withstanding
sterilization for ophthalmics
64
Packaging Guidelines Parenteral Glass
ampules and vials The information of the
manufacturers name, the glass type, a physical
description of the container, its chemical
resistance, its light transmission
Compatibility with contents which includes
leaching and/or migration tests, sampling plan
and acceptance. Plastic vials The
information of the manufacturers name, the
plastic type, its composition, the method of
manufacture, analytical controls light
transmission, certain USP tests, vapor
transmission. Compatibility with contents
which includes leaching and/or migration tests, a
sampling plan and acceptance.
65
Nonparenteral The guidelines for glass
and plastic bottles are similar to glass and
parenteral containers, but a description of the
desiccant, if present. Glass Type
I borosilicate glass, containing 80 silicon
dioxide and 10 B2O3 with smaller amounts of
Al2O3 and Na2O Type II de-alkalized
soda-lime glass with higher level of Na2O
(1317) and CaO (511) Type III
containing sodium and calcium oxide levels like
Type II but contains more leachable oxides of
other elements.
66
Advantages Impermeable all gases,
excellent clarity, easy clean and sterilize with
heat, inert material, variety of shapes,
filling-friendly, good compresssional strength,
hot filled Disadvantages Density22.5
g/cc, brittle character more expensive
Metal Tinplate tin coating to sheet
steel Aluminum 10 mils for rigid
containers (1 mil 1/1000 inch)
3-5 mils for semirigid foil
containers 1 mil for
blister construction
0.3 mils for foil in laminates
67
Plastics Advantages light,
1-1.5 g/cc manufacturing complex
container design freedom
shatter-proof crystal
clear or totally opaque heat
sealing, readily printing inks
less expensive Disadvantages
gas permeability, not inert
Stress cracking in the presence of alcohols

68
Disadvantages Gas permeability,
not inert Stress cracking in the
presence of alcohols, organic acids,
ethers and may oils
Heat, sunlight and oxygen sensitive
Poor conductors of electricity
Leaching additives
Plastic Materials Polyethylene (PE), Polyvinyl
chloride (PVC), Polypropylene (PP),
Polyvinylidene chloride (PVDC), Polystyrene (PS),
Fluorine-containing polymers, Polyurethane
69
(No Transcript)
70
Polyethylene (PE) High density polyethylene
(HDPE) 0.95-0.97 Low density polyethylene
(LDPE) 0.91-0.93
Property LDPE
HDPE Density g/cc
0.91-0.925
0.945-0.967 Tensile Strength, kpsi
1.2-2.5 3.0-7.5 Tensile
Modulus 1 Secant, kpsi
20-40 125 Haze,
4-10
25-50 WVTR, g.mil/100 in2 day 100 F 90
RH 1.2
0.3-0.65
71
Fluorine-containing polymers PTFE
polytetrafluoroethylene Teflon, used in drug
packaging, as a liner for rubber stoppers.
ACLAR polymer of trichlorofluoroethylene, used
in drug packaging as a laminate width PVC in
blister packages. Polyurethane Foamed
polyurethane used for tablet bottle stuffing
USP Package Designation Well-closed
container Tight container Hermetic
container
72
USP Package Designation Well-closed
container Tight container Hermetic
container Light resistant container
Single unit container Single dose container
Unit dose container Multiple dose
container
73
Compatibility Interaction of a drug and
the package Reduction in drug availability
or potency through sorption Contamination as
the formulation extract substances from the
package Breakdown of the package by
deterioration of its strength, stiffness or
barrier properties as the formulation chemically
attacks the package Sorption can change
product potency Leaching can cause
pharmaceutical products to discolor precipitate,
change pH, and became contaminated.
Container modification can lead to container
breakdown and product leakage.
74
(3). Process Development, Proposed Product Pilot
Testing, Stability Studies, Master Batch
Documentation Process Development, Proposed
Product Pilot Testing example Tablets
Solid-solid mixing, solid-liquid mixing,
milling, or size reduction, drying, and
compaction Selection of the formulation
components and equipment
75
Optimization of the efficiency of the unit
process Review of the formula each
ingredient and its contribution need be
understood Raw materials active
ingredientssupplier Relevant
processing equipment relevant to production
size Production rates consideration of
the future market requirements
76
Process Evaluation Order of addition of
components, including adjustment of their
amounts Mixing speed, Mixing time
Rate of addition of granulation agents, solvents,
solutions of drugs, slurries Heating and
cooling rates Filter sizes (liquids)
Screen sizes (solids) Drying
temperatures, Drying time Stability Studies,
Master Batch Documentation Development